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J. Biol. Chem., Vol. 280, Issue 46, 38478-38488, November 18, 2005

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A Role for the Distal Carboxyl Tails in Generating the Novel Pharmacology and G Protein Activation Profile of µ and Opioid Receptor Hetero-oligomers^*

Theresa Fan, George Varghese, Tuan Nguyen, Roderick Tse, Brian F. O'Dowd, and Susan R. George, Canada Research Chair in Molecular Neuroscience¶1

From the Departments of Pharmacology and ^¶Medicine, University of Toronto, Toronto, Ontario M5S 1A8 and The Centre for Addiction and Mental Health, Ontario M5T 1R8, Canada

Opioid receptor pharmacology in vivo has predicted a greater number of receptor subtypes than explained by the profiles of the three cloned opioid receptors, and the functional dependence of the receptors on each other shown in gene-deleted animal models remains unexplained. One mechanism for such findings is the generation of novel signaling complexes by receptor hetero-oligomerization, which we previously showed results in significantly different pharmacology for µ and receptor hetero-oligomers compared with the individual receptors. In the present study, we show that deltorphin-II is a fully functional agonist of the µ- heteromer, which induced desensitization and inhibited adenylyl cyclase through a pertussis toxin-insensitive G protein. Activation of the µ- receptor heteromer resulted in preferential activation of G_z, illustrated by incorporation of GTP³⁵S, whereas activation of the individually expressed µ and receptors preferentially activated G_i. The unique pharmacology of the µ- heteromer was dependent on the reciprocal involvement of the distal carboxyl tails of both receptors, so that truncation of the distal µ receptor carboxyl tail modified the -selective ligand-binding pocket, and truncation of the receptor distal carboxyl tail modified the µ-selective binding pocket. The distal carboxyl tails of both receptors also had a significant role in receptor interaction, as evidenced by the reduced ability to co-immunoprecipitate when the carboxyl tails were truncated. The interaction between µ and receptors occurred constitutively when the receptors were co-expressed, but did not occur when receptor expression was temporally separated, indicating that the hetero-oligomers were generated by a co-translational mechanism.

Received for publication, May 23, 2005 , and in revised form, September 12, 2005.

^* The work was supported in part by the U.S. National Institute on Drug Abuse and the Canadian Institutes for Health Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Medical Sciences Bldg., Rm. 4358, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada. Tel.: 416-978-3367; Fax: 416-971-2868; E-mail: s.george{at}utoronto.ca.

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